Novel chromen-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

ABSTRACT

This invention relates to novel chromen-2-one derivatives of Formula (I) useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

TECHNICAL FIELD

This invention relates to novel chromen-2-one derivatives useful asmonoamine neurotransmitter re-uptake inhibitors.

In other aspects the invention relates to the use of these compounds ina method for therapy and to pharmaceutical compositions comprising thecompounds of the invention.

BACKGROUND ART

Serotonin Selective Reuptake Inhibitors (SSRIs) currently provideefficacy in the treatment of several CNS disorders, including depressionand panic disorder. SSRIs are generally perceived by psychiatrists andprimary care physicians as effective, well-tolerated and easilyadministered. However, they are associated with a number of undesirablefeatures.

Thus, there is still a strong need for compounds with an optimisedpharmacological profile as regards the activity on reuptake of themonoamine neurotransmitters serotonin, dopamine and noradrenaline, suchas the ratio of the serotonin reuptake versus the noradrenaline anddopamine reuptake activity.

WO 2006/035034 and WO 2007/093604 (both NeuroSearch A/S) disclosechromen-2-one derivatives and their use as monoamine neurotransmitterre-uptake inhibitors.

SUMMARY OF THE INVENTION

It is an object of the invention to provide novel compounds which showactivity as monoamine neurotransmitter re-uptake inhibitors.

In its first aspect, the invention provides a compound of Formula I:

any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof,wherein R¹ and Q are as defined below.

In its second aspect, the invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof the invention, any of its stereoisomers or any mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof, togetherwith at least one pharmaceutically acceptable carrier, excipient ordiluent.

In a further aspect, the invention provides the use of a compound of theinvention, any of its stereoisomers or any mixture of its stereoisomers,or a pharmaceutically acceptable salt thereof, for the manufacture of apharmaceutical composition for the treatment, prevention or alleviationof a disease or a disorder or a condition of a mammal, including ahuman, which disease, disorder or condition is responsive to inhibitionof monoamine neurotransmitter re-uptake in the central nervous system.

In a still further aspect, the invention relates to a method fortreatment, prevention or alleviation of a disease or a disorder or acondition of a living animal body, including a human, which disorder,disease or condition is responsive to responsive to inhibition ofmonoamine neurotransmitter re-uptake in the central nervous system,which method comprises the step of administering to such a living animalbody in need thereof a therapeutically effective amount of a compound ofthe invention, any of its stereoisomers or any mixture of itsstereoisomers, or a pharmaceutically acceptable salt thereof.

Other objects of the invention will be apparent to the person skilled inthe art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION Chromen-2-one Derivatives

In its first aspect the present invention provides compounds of FormulaI:

any of its stereoisomers or any mixture of its stereoisomers,or a pharmaceutically acceptable salt thereof,wherein

Q represents a chromen-2-one-yl group;

-   -   which chromen-2-one-yl group is substituted with one heteroaryl        group;        -   which heteroaryl group is optionally substituted with one or            more substituents independently selected from the group            consisting of:            -   halo, trifluoromethyl, trifluoromethoxy, cyano, amino,                nitro, hydroxy, alkoxy, cycloalkoxy, methylenedioxy,                ethylenedioxy, alkyl, cycloalkyl, cycloalkylalkyl,                alkenyl and alkynyl;    -   and which chromen-2-one-yl group is optionally further        substituted with one or more substituents independently selected        from the group consisting of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, amino,            nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl and alkynyl;

R¹ represents hydrogen or alkyl;

-   -   which alkyl is optionally substituted with one or more        substituents independently selected from the group consisting        of:        -   halo, trifluoromethyl, trifluoromethoxy, cyano, amino,            nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,            cycloalkylalkyl, alkenyl and alkynyl.

In one embodiment of the compound of Formula I, R¹ represents hydrogenor alkyl. In a special embodiment R¹ represents hydrogen.

In a further embodiment of the compound of Formula I, Q represents asubstituted chromen-2-one-7-yl group.

In a still further embodiment of the compound of Formula I, Q representsa 3-(optionally substituted heteroaryl)-chromen-2-one-yl group.

In a further embodiment of the compound of Formula I, Q represents achromen-2-one-7-yl substituted with a furanyl or a benzofuranyl group.In a special embodiment, Q represents chromen-2-one-7-yl substitutedwith furanyl, such as furan-2-yl or furan-3-yl. In a further specialembodiment, Q represents a chromen-2-one-7-yl substituted withbenzofuranyl, such as benzofuran-2-yl.

In a special embodiment the chemical compound of the invention is

-   exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-furan-2-yl-chromen-2-one;-   exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-furan-3-yl-chromen-2-one;-   exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-benzofuran-2-yl-chromen-2-one;    or a pharmaceutically acceptable salt thereof.

Any combination of two or more of the embodiments as described above isconsidered within the scope of the present invention.

Definition of Substituents

In the context of this invention halo represents fluoro, chloro, bromoor iodo.

In the context of this invention an alkyl group designates a univalentsaturated, straight or branched hydrocarbon chain. The hydrocarbon chainpreferably contains of from one to six carbon atoms (C₁₋₆-alkyl),including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl andisohexyl. In a preferred embodiment alkyl represents a C₁₋₄-alkyl group,including butyl, isobutyl, secondary butyl, and tertiary butyl. Inanother preferred embodiment of this invention alkyl represents aC₁₋₃-alkyl group, which may in particular be methyl, ethyl, propyl orisopropyl.

In the context of this invention an alkenyl group designates a carbonchain containing one or more double bonds, including di-enes, tri-enesand poly-enes. In a preferred embodiment the alkenyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkenyl),including at least one double bond. In a most preferred embodiment thealkenyl group of the invention is ethenyl; 1- or 2-propenyl; 1-, 2- or3-butenyl, or 1,3-butadienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or1,3-hexadienyl, or 1,3,5-hexatrienyl.

In the context of this invention an alkynyl group designates a carbonchain containing one or more triple bonds, including di-ynes, tri-ynesand poly-ynes. In a preferred embodiment the alkynyl group of theinvention comprises of from two to six carbon atoms (C₂₋₆-alkynyl),including at least one triple bond. In its most preferred embodiment thealkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or3-butynyl, or 1,3-butadiynyl; 1-, 2-, 3-, 4-pentynyl, or1,3-pentadiynyl; 1-, 2-, 3-, 4-, or 5-hexynyl, or 1,3-hexadiynyl or1,3,5-hexatriynyl.

In the context of this invention a cycloalkyl group designates a cyclicalkyl group, preferably containing of from three to seven carbon atoms(C₃₋₇-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Cycloalkoxy means O-cycloalkyl, wherein cycloalkyl is as defined above.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

In the context of this invention a heteroaryl group designates anaromatic mono- or bicyclic heterocyclic group, which holds one or moreheteroatoms in its ring structure. Preferred heteroatoms includenitrogen (N), oxygen (O), and sulphur (S).

Preferred monocyclic heteroaryl groups of the invention include aromatic5- and 6-membered heterocyclic monocyclic groups, including for example,but not limited to, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,tetrazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,triazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrrolyl,pyrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, or pyridazinyl.

Preferred bicyclic heteroaryl groups of the invention include forexample, but not limited to, indolizinyl, indolyl, isoindolyl,indazolyl, benzofuranyl, benzo[b]thienyl, benzimidazolyl, benzoxazolyl,benzooxadiazolyl, benzothiazolyl, benzo[d]isothiazolyl, purinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, and indenyl.

Pharmaceutically Acceptable Salts

The chemical compound of the invention may be provided in any formsuitable for the intended administration. Suitable forms includepharmaceutically (i.e. physiologically) acceptable salts, and pre- orprodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydro-chloride, the hydrobromide, the nitrate, the perchlorate,the phosphate, the sulphate, the formate, the acetate, the aconate, theascorbate, the benzenesulphonate, the benzoate, the cinnamate, thecitrate, the embonate, the enantate, the fumarate, the glutamate, theglycolate, the lactate, the maleate, the malonate, the mandelate, themethanesulphonate, the naphthalene-2-sulphonate, the phthalate, thesalicylate, the sorbate, the stearate, the succinate, the tartrate, thetoluene-p-sulphonate, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Examples of pharmaceutically acceptable cationic salts of a chemicalcompound of the invention include, without limitation, the sodium, thepotassium, the calcium, the magnesium, the zinc, the aluminium, thelithium, the choline, the lysinium, and the ammonium salt, and the like,of a chemical compound of the invention containing an anionic group.Such cationic salts may be formed by procedures well known and describedin the art.

In the context of this invention the “onium salts” of N-containingcompounds are also contemplated as pharmaceutically acceptable salts.Preferred “onium salts” include the alkyl-onium salts, thecycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.

Examples of pre- or prodrug forms of the chemical compound of theinvention include examples of suitable prodrugs of the substancesaccording to the invention including compounds modified at one or morereactive or derivatizable groups of the parent compound. Of particularinterest are compounds modified at a carboxyl group, a hydroxyl group,or an amino group. Examples of suitable derivatives are esters oramides.

The chemical compound of the invention may be provided in dissoluble orindissoluble forms together with a pharmaceutically acceptable solventsuch as water, ethanol, and the like. Dissoluble forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, thedissoluble forms are considered equivalent to indissoluble forms for thepurposes of this invention.

Steric Isomers

It will be appreciated by those skilled in the art that the compounds ofthe present invention may exist in different stereoisomericforms—including enantiomers, diastereomers and cis-trans-isomers.

For example, the group —O-Q of Formula I may in particular be in the exoor endo configuration relative to the azabicyclic ring.

The invention includes all such stereoisomers and any mixtures thereofincluding racemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the enantiomeric compounds(including enantiomeric intermediates) is—in the case the compound beinga chiral acid—by use of an optically active amine, and liberating thediastereomeric, resolved salt by treatment with an acid. Another methodfor resolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of D- or L- (tartrates, mandelates,or camphor-sulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Labelled Compounds

The compounds of the invention may be used in their labelled orunlabelled form. In the context of this invention the labelled compoundhas one or more atoms replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. The labelling will allow easy quantitative detection of saidcompound.

The labelled compounds of the invention may be useful as diagnostictools, radio tracers, or monitoring agents in various diagnosticmethods, and for in vivo receptor imaging.

The labelled compound of the invention preferably contains at least oneradio-nuclide as a label. Positron emitting radionuclides are allcandidates for usage. In the context of this invention the radionuclideis preferably selected from ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C,¹³¹I, ¹²⁵I, ¹²³I, and ¹⁸F.

The physical method for detecting the labelled compound of the presentinvention may be selected from Position Emission Tomography (PET),Single Photon Imaging Computed Tomography (SPECT), Magnetic ResonanceSpectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed AxialX-ray Tomography (CAT), or combinations thereof.

Methods of Preparation

The chemical compounds of the invention may be prepared by conventionalmethods for chemical synthesis, e.g. those described in the workingexamples. The starting materials for the processes described in thepresent application are known or may readily be prepared by conventionalmethods from commercially available chemicals.

Also one compound of the invention can be converted to another compoundof the invention using conventional methods.

The end products of the reactions described herein may be isolated byconventional techniques, e.g. by extraction, crystallisation,distillation, chromatography, etc.

Biological Activity

Compounds of the invention may be tested for their ability to inhibitreuptake of the monoamines dopamine, noradrenaline and serotonin insynaptosomes e.g. such as described in WO 97/30997 (NeuroSearch A/S).Based on the balanced activity observed in these tests the compound ofthe invention is considered useful for the treatment, prevention oralleviation of a disease or a disorder or a condition of a mammal,including a human, which disease, disorder or condition is responsive toinhibition of monoamine neurotransmitter re-uptake in the centralnervous system.

In a special embodiment, the compounds of the invention are considereduseful for the treatment, prevention or alleviation of: mood disorder,depression, atypical depression, depression secondary to pain, majordepressive disorder, dysthymic disorder, bipolar disorder, bipolar Idisorder, bipolar II disorder, cyclothymic disorder, mood disorder dueto a general medical condition, substance-induced mood disorder,pseudodementia, Ganser's syndrome, obsessive compulsive disorder, panicdisorder, panic disorder without agoraphobia, panic disorder withagoraphobia, agoraphobia without history of panic disorder, panicattack, memory deficits, memory loss, attention deficit hyperactivitydisorder, obesity, anxiety, generalized anxiety disorder, eatingdisorder, Parkinson's disease, parkinsonism, dementia, dementia ofageing, senile dementia, Alzheimer's disease, Down's syndrome, acquiredimmunodeficiency syndrome dementia complex, memory dysfunction inageing, specific phobia, social phobia, social anxiety disorder,post-traumatic stress disorder, acute stress disorder, chronic stressdisorder, drug addiction, drug abuse, drug abuse liability, cocaineabuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism,kleptomania, withdrawal symptoms caused by termination of use ofaddictive substances, pain, chronic pain, inflammatory pain, neuropathicpain, diabetic neuropathic pain, migraine pain, tension-type headache,chronic tension-type headache, pain associated with depression,fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, backpain, cancer pain, irritable bowel pain, irritable bowel syndrome,post-operative pain, post-mastectomy pain syndrome (PMPS), post-strokepain, drug-induced neuropathy, diabetic neuropathy,sympathetically-maintained pain, trigeminal neuralgia, dental pain,myofacial pain, phantom-limb pain, bulimia, premenstrual syndrome,premenstrual dysphoric disorder, late luteal phase syndrome,post-traumatic syndrome, chronic fatigue syndrome, persistent vegetativestate, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities. Ina preferred embodiment, the compounds are considered useful for thetreatment, prevention or alleviation of depression.

It is at present contemplated that a suitable dosage of the activepharmaceutical ingredient (API) is within the range of from about 0.1 toabout 1000 mg API per day, more preferred of from about 10 to about 500mg API per day, most preferred of from about 30 to about 100 mg API perday, dependent, however, upon the exact mode of administration, the formin which it is administered, the indication considered, the subject andin particular the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

Preferred compounds of the invention show a biological activity in thesub-micromolar and micromolar range, i.e. of from below 1 to about 100μM.

Pharmaceutical Compositions

In another aspect the invention provides novel pharmaceuticalcompositions comprising a therapeutically effective amount of thechemical compound of the invention.

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers, and, optionally, othertherapeutic and/or prophylactic ingredients, known and used in the art.The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not harmful to therecipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).

A therapeutically effective dose refers to that amount of activeingredient, which ameliorates the symptoms or condition. Therapeuticefficacy and toxicity, e.g. ED₅₀ and LD₅₀, may be determined by standardpharmacological procedures in cell cultures or experimental animals. Thedose ratio between therapeutic and toxic effects is the therapeuticindex and may be expressed by the ratio LD₅₀/ED₅₀. Pharmaceuticalcompositions exhibiting large therapeutic indexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depends on the nature and severity of the diseasebeing treated, and is within the discretion of the physician, and may bevaried by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect. However, it ispresently contemplated that pharmaceutical compositions containing offrom about 0.1 to about 500 mg of active ingredient per individual dose,preferably of from about 1 to about 100 mg, most preferred of from about1 to about 10 mg, are suitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.1 μg/kg i.v. and 1 μg/kg p.o. The upper limit of thedosage range is presently considered to be about 10 mg/kg i.v. and 100mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Methods of Therapy

In another aspect the invention provides a method for the treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disease, disorder orcondition is responsive to inhibition of monoamine neurotransmitterre-uptake in the central nervous system, and which method comprisesadministering to such a living animal body, including a human, in needthereof an effective amount of a chemical compound of the invention.

It is at present contemplated that suitable dosage ranges are 0.1 to1000 milligrams daily, 10-500 milligrams daily, and especially 30-100milligrams daily, dependent as usual upon the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightof the subject involved, and further the preference and experience ofthe physician or veterinarian in charge.

EXAMPLES

The invention is further illustrated with reference to the followingexamples, which are not intended to be in any way limiting to the scopeof the invention as claimed.

Preparatory Examples

All reactions involving air sensitive reagents or intermediates wereperformed under nitrogen and in anhydrous solvents. Magnesium sulphatewas used as drying agent in the workup-procedures and solvents wereevaporated under reduced pressure.

Example 1

endo-Benzoic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester

Benzoylchloride (84.3 g, 600 mmol) was added during 30 min at <30° C. toa mixture of tropine (70.6 g, 500 mmol), potassium tert-butoxide (67.3g, 600 mmol) and THF (500 ml). The mixture was stirred at roomtemperature for 2 h. Water (1 L) was added followed by extraction withdiethylether (2×500 ml). The organic phase was washed twice with water(2×200 ml) followed by a solution of saturated aqueous sodium chloride(200 ml). The ether phase was dried and hydrochloric acid in ethanol(170 ml, 3 M) was added. The precipitated hydrochloride was filtered andwashed with diethylether. The free base was obtained by adding an excessof aqueous ammonia followed by extraction with a mixture of ethylacetateand diethylether. Yield 66.8 g (54%).

endo-Benzoic acid 8-aza-bicyclo[3.2.1]oct-3-yl ester

2,2,2-Trichloroethylchloroformate (75.0 ml, 544 mmol) was added dropwiseto a mixture of endo-benzoic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylester (66.8 g, 272 mmol) and dry toluene (500 ml). The mixture wasallowed to stir for 1 h at room temperature, followed by 15 h at 100° C.Water (250 ml) was added followed by stirring 1 h. The phases wereseparated and the organic phase was washed twice with water (2×200 ml).The mixture of the intermediate3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtrichloromethyl ester, was dried and evaporated. Acetic acid (350 ml)was added followed by addition of zinc (53.4 g, 817 mmol) over 3 h timeperiod. Water (100 ml) was added, cooled by adding ice and made alkalineby adding concentrated aqueous ammonia (ca: 400 ml) and the mixture wasextracted with dichloromethane (2×300 ml). Yield 44.5 g (61%).

endo-3-Benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

Di-tert-butyl-dicarbonate (39.9 g, 183 mmol) solved in THF (100 ml) wasadded to a stirred mixture of endo-benzoic acid8-aza-bicyclo[3.2.1]oct-3-yl ester (44.5 g, 166.4 mmol), triethylamine(67.4 g, 666 mmol) and THF (250 ml) during 0.5 h at room temperature,followed by stirring for 1 h. Water (1 L) was added and the mixture wasextracted with diethylether (2×300 ml). The collected ether phase waswashed twice with water (2×200 ml), dried and evaporated. Yield 60.1 g(100%).

endo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester

A mixture of endo-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g199 mmol) and ethanol (99%, 400 ml) was stirred for 3 days at roomtemperature. Potassium benzoate was separated by filtration and thefiltrate was evaporated. Diethylether (200 ml) was added and remainingpotassium benzoate was separated by filtration and the filtrate wasevaporated. The product was triturated with petroleum. Yield 30.0 g(80%). Mp 139.5-140.8° C.

exo-7-(8-tert-Butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one

Triphenylphosphine (7.5 g, 28.6 mmol) was solved in dioxane (70 ml) andcooled to 8° C. Diethylazodicarboxylate (5.0 g, 28.6 mmol) was added tothe mixture below 15° C., followed by stirring for 15 minutes.endo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester (5.0 g, 22.0 mmol) and 7-hydroxycoumarine (4.3 g, 26.4 mmol) wasadded to the mixture. The temperature raised due to an exothermicreaction. The mixture was allowed to stir for 15 h at room temperature.Water (200 ml) was added followed by extraction with diethylether (2×100ml). The mixture was dried and evaporated. Chromatography on silica gelwith dichloromethane and 5% methanol as solvent. The crude product wassolved in diethylether (200 ml) and washed with aqueous sodium hydroxide(3×200 ml, 1 M). The product was dried and evaporated. Yield 5.32 g(65%).

exo-7-[(1S,3S,5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-bromo-chromen-2-one

Bromine (1.38 ml, 27.0 mmol) was added to a mixture ofexo-7-(8-tert-butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one(7.8 g, 21.0 mmol), acetic acid (150 ml) and sodium acetate (5.2 g, 63.0mmol). The mixture was stirred for 90 min at room-temperature. Water(100 ml) was added. The precipitation was filtered and washed with water(10 ml), methanol (5 ml) and diethylether (20 ml). Yield 7.5 g (79%).

Method Aexo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-furan-2-yl-chromen-2-onehydrochloric acid salt

A mixture ofexo-7-[(1S,3S,5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-bromo-chromen-2-one(2.0 g, 4.0 mmol), 2-furanboronic acid (0.89 g, 8.0 mmol), potassiumcarbonate (1.66 g, 12.0 mmol), 1,2-dimethoxyethane (20 ml) and water (10ml) was stirred and perfused with argon for 10 min. Palladacycle (94 mg,0.1 mmol) and Pd(PPh₃)₄ (115 mg, 0.1 mmol) was added followed bystirring at reflux for 2 h. The mixture was allowed to cool to roomtemperature. Water (25 ml) was added and the precipitated solid wasfiltered. A mixture of the solid and hydrogen chloride in acetic acid(20 ml, 1 M) was stirred for 3 h. The mixture was made alkaline byadding aqueous ammonia. The product precipitated. Chromatography onsilica gel with dichloromethane, 10% methanol and 1% aqueous ammonia assolvent gave the pure free base. The compound was converted to thecorresponding salt by stirring in hydrogen chloride in acetic acid (5ml, 1 M). Yield 150 mg (12%). LC-ESI-HRMS of [M+H]+ shows 338.1389 Da.Calc. 338.139234 Da, dev. −1 ppm.

exo7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-furan-3-yl-chromen-2-onehydrochloric acid salt

Was prepared according to method A fromexo-7-[(1S,3S,5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-bromo-chromen-2-oneand 3-furanboronic acid. LC-ESI-HRMS of [M+H]+ shows 338.1406 Da. Calc.338.139234 Da, dev. 4 ppm.

exo7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-benzofuran-2-yl-chromen-2-onehydrochloric acid salt

Was prepared according to method A fromexo-7-[(1S,3S,5R)-(8-tert-butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-bromo-chromen-2-oneand 2-benzofuranboronic acid. LC-ESI-HRMS of [M+H]+ shows 388.1554 Da.Calc. 388.154884 Da, dev. 1.3 ppm.

Test Example In Vitro Inhibition Activity

A number of compounds were tested for their ability to inhibit thereuptake of the monoamine neurotransmitters dopamine (DA), noradrenaline(NA) and serotonine (5-HT) in synaptosomes as described in WO 97/16451.

The test values are given as IC₅₀ (the concentration (μM) of the testsubstance which inhibits the specific binding of ³H-DA, ³H-NA, or³H-5-HT by 50%).

Test results obtained by testing selected compounds of the presentinvention appear from the below table:

TABLE 1 5-HT-uptake DA-uptake NA-uptake Test compound IC₅₀(μM) IC₅₀(μM)IC₅₀(μM) 1^(st) Compound of Method A: 0.0077 0.034 0.0043exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]-oct-3-yl)oxy]-3-furan-2-yl-chromen-2-one 2^(nd) Compound of Method A:0.010 0.0099 0.00048 exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]-oct-3-yl)oxy]-3-furan-3-yl-chromen-2-one 3^(rd) Compound of Method A:0.0091 0.70 0.84 exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]-oct-3-yl)oxy]-3-benzofuran-2-yl-chromen- 2-one

1-13. (canceled)
 14. A compound of Formula I:

any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof, wherein Q represents achromen-2-one-yl group; which chromen-2-one-yl group is substituted withone heteroaryl group; which heteroaryl group is optionally substitutedwith one or more substituents independently selected from the groupconsisting of: halo, trifluoromethyl, trifluoromethoxy, cyano, amino,nitro, hydroxy, alkoxy, cycloalkoxy, methylenedioxy, ethylenedioxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; and whichchromen-2-one-yl group is optionally further substituted with one ormore substituents independently selected from the group consisting of:halo, trifluoromethyl, trifluoromethoxy, cyano, amino, nitro, hydroxy,alkoxy, cycloalkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl andalkynyl; R¹ represents hydrogen or alkyl; which alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of: halo, trifluoromethyl, trifluoromethoxy, cyano,amino, nitro, hydroxy, alkoxy, cycloalkoxy, alkyl, cycloalkyl,cycloalkylalkyl, alkenyl and alkynyl.
 15. The chemical compound of claim14, any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof wherein R¹ represents hydrogenor alkyl.
 16. The chemical compound of claim 14, any of itsstereoisomers or any mixture of its stereoisomers, or a pharmaceuticallyacceptable salt thereof, wherein Q represents a substitutedchromen-2-one-7-yl group.
 17. The chemical compound of claim 14, any ofits stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof wherein Q represents a3-(optionally substituted heteroaryl)-chromen-2-one-yl group.
 18. Thechemical compound of claim 14, any of its stereoisomers or any mixtureof its stereoisomers, or a pharmaceutically acceptable salt thereofwherein Q represents chromen-2-one-7-yl substituted with a furanyl or abenzofuranyl group.
 19. The chemical compound of claim 14, which isexo-7-[(1S,3S5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-furan-2-yl-chromen-2-one;exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-furan-3-yl-chromen-2-one;exo-7-[(1S,3S,5R)-(8-Aza-bicyclo[3.2.1]oct-3-yl)oxy]-3-benzofuran-2-yl-chromen-2-one;any of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable salt thereof.
 20. A pharmaceutical composition, comprising atherapeutically effective amount of a compound of claim 14, any of itsstereoisomers or any mixture of its stereoisomers, or a pharmaceuticallyacceptable salt thereof, together with at least one pharmaceuticallyacceptable carrier, excipient or diluent.
 21. A method for treatment,prevention or alleviation of a disease or a disorder or a condition of aliving animal body, including a human, which disorder, disease orcondition is responsive to inhibition of monoamine neurotransmitterre-uptake in the central nervous system, which method comprises the stepof administering to such a living animal body in need thereof atherapeutically effective amount of a compound according to claim 14, orany of its stereoisomers or any mixture of its stereoisomers, or apharmaceutically acceptable salt thereof.
 22. The method according toclaim 21, wherein the disease, disorder or condition is mood disorder,depression, atypical depression, depression secondary to pain, majordepressive disorder, dysthymic disorder, bipolar disorder, bipolar Idisorder, bipolar II disorder, cyclothymic disorder, mood disorder dueto a general medical condition, substance-induced mood disorder,pseudodementia, Gianser's syndrome, obsessive compulsive disorder, panicdisorder, panic disorder without agoraphobia, panic disorder withagoraphobia, agoraphobia without history of panic disorder, panicattack, memory deficits, memory loss, attention deficit hyperactivitydisorder, obesity, anxiety, generalized anxiety disorder, eatingdisorder, Parkinson's disease, parkinsonism, dementia, dementia ofageing, senile dementia, Alzheimer's disease, Down's syndrome, acquiredimmunodeficiency syndrome dementia complex, memory dysfunction inageing, specific phobia, social phobia, social anxiety disorder,post-traumatic stress disorder, acute stress disorder, chronic stressdisorder, drug addiction, drug abuse, drug abuse liability, cocaineabuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism,kleptomania, withdrawal symptoms caused by termination of use ofaddictive substances, pain, chronic pain, inflammatory pain, neuropathicpain, diabetic neuropathic pain, migraine pain, tension-type headache,chronic tension-type headache, pain associated with depression,fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, backpain, cancer pain, irritable bowel pain, irritable bowel syndrome,post-operative pain, post-mastectomy pain syndrome (PMPS), post-strokepain, drug-induced neuropathy, diabetic neuropathy,sympathetically-maintained pain, trigeminal neuralgia, dental pain,myofacial pain, phantom-limb pain, bulimia, premenstrual syndrome,premenstrual dysphoric disorder, late luteal phase syndrome,post-traumatic syndrome, chronic fatigue syndrome, persistent vegetativestate, urinary incontinence, stress incontinence, urge incontinence,nocturnal incontinence, sexual dysfunction, premature ejaculation,erectile difficulty, erectile dysfunction, premature female orgasm,restless leg syndrome, periodic limb movement disorder, eatingdisorders, anorexia nervosa, sleep disorders, pervasive developmentaldisorders, autism, Asperger's disorder, Rett's disorder, childhooddisintegrative disorder, learning disabilities, motor skills disorders,mutism, trichotillomania, narcolepsy, post-stroke depression,stroke-induced brain damage, stroke-induced neuronal damage, Gilles dela Tourettes disease, tinnitus, tic disorders, body dysmorphicdisorders, oppositional defiant disorder or post-stroke disabilities.